Inhibition of Caspases Prevents Ototoxic and Ongoing Hair Cell Death

Matsui, Jonathan I.; Ogilvie, Judith Mosinger; Warchol, Mark E.

doi:10.1523/jneurosci.22-04-01218.2002

Cited by 128 publications

(140 citation statements)

References 76 publications

(93 reference statements)

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“…Our in vitro results obtained with postnatal cochlear cultures showed little or no evidence of hair cell damage following 24 h treatment with 0.25% DMSO or less. These results are consistent with two previous reports that used 0.1% DMSO and found no negative side effects (Lee et al, 2001;Matsui et al, 2002). A 0.5% DMSO concentration caused a slight increase in IHC ( Figure 2C, G).…”

Section: Discussionsupporting

confidence: 93%

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

2008

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The amphipathic molecule dimethyl sulphoxide (DMSO) is a solvent often used to dissolve compounds applied to the inner ear; however, little is known about its potential cytotoxic side effects. To address this question, we applied 0.1 to 6% DMSO for 24 h to cochlear organotypic cultures from postnatal day 3 rats and examined its cytotoxic effects. DMSO concentrations of 0.1% and 0.25% caused little or no damage. However, concentrations between 0.5 and 6% resulted in stereocilia damage, hair cell swelling and a dose-dependent loss of hair cells. Hair cell damage began in the basal turn of the cochlea and spread towards the apex with increasing concentration. Surprisingly, DMSO-induced damage was greater for inner hair cells than outer hair cell whereas nearby supporting cells were largely unaffected. Most hair cell death was associated with nuclear shrinkage and fragmentation, morphological features consistent with apoptosis. DMSO treatment induced TUNEL positive staining in many hair cells and activated both initiator caspase-9 and caspase-8 and executioner caspase-3; this suggests that apoptosis is initiated by both intrinsic mitochondrial and extrinsic membrane cell death signaling pathways.

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Section: Discussionsupporting

confidence: 93%

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

2008

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“…Spontaneous HC loss was likely caused by the explantation process or deficiencies in culture conditions. HC death might be prevented by inhibiting molecules in the apoptotic pathway, such as caspases, as has been accomplished in cultures of whole utricles from chickens (Matsui et al 2002) and mice (Cunningham et al 2002).…”

Section: Patterns Of Hc Loss Vary In Control and Streptomycin-treatedmentioning

confidence: 99%

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Shang

Cafaro

Nehmer

et al. 2010

JARO

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In chickens, nonsensory supporting cells divide and regenerate auditory hair cells after injury. Anatomical evidence suggests that supporting cells can also transdifferentiate into hair cells without dividing. In this study, we characterized an organ culture model to study auditory hair cell regeneration, and we used these cultures to test if direct transdifferentiation alone can lead to significant hair cell regeneration. Control cultures (organs from posthatch chickens maintained without streptomycin) showed complete hair cell loss in the proximal (high-frequency) region by 5 days. In contrast, a 2-day treatment with streptomycin induced loss of hair cells from all regions by 3 days. Hair cell regeneration proceeded in culture, with the time course of supporting cell division and hair cell differentiation generally resembling in vivo patterns. The degree of supporting cell division depended upon the presence of streptomycin, the epithelial region, the type of culture media, and serum concentration. On average, 87% of the regenerated hair cells lacked the cell division marker BrdU despite its continuous presence, suggesting that most hair cells were regenerated via direct transdifferentiation. Addition of the DNA polymerase inhibitor aphidicolin to culture media prevented supporting cell division, but numerous hair cells were regenerated nonetheless. These hair cells showed signs of functional maturation, including stereociliary bundles and rapid uptake of FM1-43. These observations demonstrate that direct transdifferentiation is a significant mechanism of hair cell regeneration in the chicken auditory after streptomycin damage in vitro.

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“…While many drugs have been demonstrated to successfully protect hair cells against damage (e.g., antioxidants, caspase inhibitors, Stat-1, etc. ; Matsui et al 2002;Wang et al 2003Wang et al , 2004Sha et al 2006;Campbell et al 2007;Schmitt et al 2009), there is currently no FDA-approved drug used for the prevention of hearing loss. Aspirin was demonstrated to protect against aminoglycoside-induced hair cell death (Sha et al 2006), but required high daily doses (3 g/day).…”

Section: Introductionmentioning

confidence: 99%

Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line

Keating

et al. 2012

JARO

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We have previously published results from a screen of 1,040 FDA-approved drugs and bioactives (NINDS Custom Collection) for drugs that protect against neomycin-induced hair cell death (Ou et al., J Assoc Res Otolaryngol 10:191-203, 2009). Further evaluation of this drug library identified eight protective drugs that shared a common quinoline scaffold. These drugs were tested further in terms of their protection against other aminoglycosides, as well as their effect on aminoglycoside uptake. All of the eight quinolines that protected against neomycin were found to protect against shortand long-term gentamicin damage protocols. We then tested the structurally related compounds quinoline, isoquinoline, naphthalene, and indole for protective effects. Of these compounds, indole demonstrated a small but significant amount of protection against neomycin, while quinoline and isoquinoline partially protected against long-term gentamicin damage. We examined whether the protective activity of this group of compounds was related to known targets of the quinoline derivatives. The protective effects did not seem linked to either the cholinergic or histaminergic pathways that are regulated by some members of the quinoline family. However, all eight protective drugs were found to reduce the uptake of aminoglycosides into hair cells. Subsequent experiments suggest that reduction of uptake is the primary mechanism of protection among the quinoline drugs.

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Inhibition of Caspases Prevents Ototoxic and Ongoing Hair Cell Death

Cited by 128 publications

References 76 publications

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures

Supporting Cell Division Is Not Required for Regeneration of Auditory Hair Cells After Ototoxic Injury In Vitro

Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line

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